PROJECT SUMMARY/ABSTRACT Ovarian cancer is the most common cause of gynecologic cancer death in the U.S. and is responsible for approximately 14,000 deaths each year in the US. Recurrent disease remains incurable and has a dismal prognosis. There is an urgent need for novel therapies. We have demonstrated that engineered measles virus (MV) strains have significant antitumor activity against ovarian cancer lines and xenografts. Their tumor specificity is due to abundant expression of the measles virus receptors CD46 and Nectin-4 in ovarian cancer. Our group was the first to translate this approach into two phase I clinical trials of MV derivatives expressing human carcinoembryonic antigen, MV-CEA (CEA added to facilitate monitoring of viral gene expression) or NIS (imaging marker of virus replication) in recurrent ovarian cancer patients. Despite the fact that study patients were platinum and taxane resistant and heavily pretreated, there was evidence of biologic activity, as indicated by CA-125 decreases, dose dependent disease stabilization, and an overall survival (OS) of 26.6 mo for patients receiving viral doses at 108 TCID50 or higher. In proof-of-principle studies, we demonstrated that MV delivery using mesenchymal stem cells (MSC) as carriers can further improve efficacy by protecting the virus from antibody neutralization and facilitate homing in tumor sites. We propose to test this novel approach in a phase I/II trial in patients with platinum resistant recurrent ovarian cancer. This innovative clinical trial proposal represents first in human testing of cell carriers for viral delivery, and has the following goals: 1) to assess the safety and efficacy of MSC delivered MV-NIS (MV-NIS/MSC) in patients with recurrent platinum resistant ovarian cancer; 2) to characterize viral gene expression following IP administration of MV-NIS/MSC, as assessed by NIS expression on imaging, to assess viral distribution/shedding, and to evaluate tumor biomarkers that can predict the therapeutic effect of this approach; and 3) to characterize the role of the immune system in determining the efficacy of MV-NIS/MSC virotherapy against ovarian cancer.